The hypothesis underlying this proposal is that "regulatory" proteins, including interleukin-4 (IL-4), transforming growth factor beta (TGFbeta), interleukin-10 (IL-10), and/or products that bind TNFalpha including single chain variable fragments of monoclonal anti-TNFalpha or the soluble forms of the TNF receptor, delivered to "autoimmune"lesions in EAE by retroviral gene transduction of "autoimmune" T cells with be therapeutic and ameliorate the disease. Studies outlined in this grant initially seek to examine this hypothesis by targeting "regulatory" proteins to lesions of EAE through adoptive transfer of transduced T cells obtained from MBP- reactive TCR transgenic mice. If adoptive transfer studies are successful, targeted gene delivery using retroviral constructs in which the IL-2 ligand has been incorporated into the retroviral coat protein as a "targeting" ligand for activated (CD25+) T cells will be attempted. Initial retargeting strategies will be attempted in vitro. If successful, these studies will be expanded in vivo in an attempt to target inflammatory T cells in lesions of EAE. There are five specific aims directed at: (1) vector development, retargeting methodology, and; (5) immunotherapy in vivo. The significance of these studies lies in their potential adaptation to immunotherapy not only of multiple sclerosis, but of other inflammatory autoimmune diseases.